The inhibition of monoacylglycerol lipase responsible for 2-AG breakdown restores the impaired CB1R-dependent LTD in MK-801-treated slices.
We reasoned that the impaired LTD may be partially explained by insufficient production or accelerated breakdown of 2-AG during synaptic stimulation. Previous studies have documented increased activity of monoacylglycerol lipase (MAGL), the enzyme responsible for 2-AG degradation, in schizophrenic individuals and experimental models of schizophrenia (Du et al., 2013; Kaya et al., 2019). Therefore, we examined whether increasing 2-AG signaling by inhibiting MAGL activity might restore the electric induction of LTD in the MK-801-treated slices. For these experiments, MK-801-treated slices were perfused with the irreversible MAGL inhibitor, JZL 184 (1 µM, perfused for the last 10 minutes of the baseline response and the first 5 minutes during LFS). Before LFS, the application of JZL 184 did not modify the baseline response. More importantly, JZL 184 reverted the loss of LTD at the MPP – DG synapse of the MK-801-treated slices for up to 90 min (fEPSP 90 min post-LFS: 58.46 ± 11.68 % of baseline, n = 5 slices / 5 animals, Student’s t-test: t(9) = 2.94, P< 0.01 vs. MK-801; traces and blue bars in Figure 5a-c). Perfusion of DCG-IV at the end of the recordings corroborated the MPP origin of the synaptic response (fEPSP in the presence of DCG-IV: 27 ± 7.43% of baseline). Likewise, induction of MPP LTD in the MK-801-treated slices was accompanied by increased MP PPF (PPR in control condition: 1.38 ± 1.11; at 90 min post-LFS: 1.77 ± 0.09; paired Student’s t-test: t(4) = 2.97, P < 0.05; blue bars in Figure 5d), which exhibited similar facilitation magnitude to the control slices (see black bars in Figure 3f). The cumulative probability chart in Figure 5e summarizes the magnitude of the MPP LTD observed in the JZL 184-treated slices (blue line) and the lack of LTD in the MK-801-treated slices (red line). These findings demonstrate that LTD induction in the MPP – DG synapse of animals treated with MK-801 is restored by using MAGL blockade to reduce 2-AG breakdown and thus enhance its signaling. This supports the notion that MAGL blockade has potentially neuroprotective effects (Ren et al., 2020).